Extensive research has been conducted over the past years to extract or synthesize new whitening agents to be used in cosmetic and dermatological compositions in order to alleviate skin pigmentation defects such as senile lentigo or chloasma or to satisfy consumers who are eager to have the lightest possible complexion.
Various whitening agents acting on melanogenesis have been proposed to this end. Among them, however, some only show a slight melanogenesis-inhibiting effect failing to provide a sufficient whitening effect, while others, which are more effective, have proven not to be free of side effects on account of their toxicity to human skin cells, rendering their use quite hazardous in cosmetics. This toxicity arises from the fact that they interfere with fundamental mechanisms of melanogenesis, by killing cells and thus forcing the skin to eliminate them while producing toxins.
For instance, hydroquinone is a compound which is particularly irritant and cytotoxic to melanocytes, and whose total or partial replacement has been contemplated by many investigators. In order to overcome the drawbacks mentioned above, it has been suggested, for example, to use derivatives of active compounds such as fatty acid esters or glycosyl ethers of hydroquinone as depigmenting agents. Unfortunately, although more photostable and less toxic than hydroquinone, these derivatives, such as arbutin, are less active than hydroquinone to improve the aspect of pigmentary defects.
Other substances have been sought which are not involved in the mechanism of melanogenesis, but which act upstream on tyrosinase by preventing its activation, and are consequently much less toxic. Tyrosinase is regarded as the key enzyme in melanin synthesis, and catalyses the first two reactions, the hydroxylation of L-tyrosine to 3,4-dihydrophenylalanine (DOPA) and the oxidation of DOPA to DOPAquinone. Kojic acid is commonly used as a tyrosinase-activation inhibitor by complexing the copper present in the active site of the enzyme. Unfortunately, this compound can give rise to allergic reactions (Nakagawa et al, in Contact Dermatitis, 1995). In addition, this compound is unstable in solution, which somewhat complicates the manufacture of a composition containing it.
Other whitening agents acting on tyrosinase activity are plant extracts, the efficacy of which is not always satisfactory. A possible explanation for the limited efficacy of these known whitening agents is that they lack proper access to tyrosinase inside the melanosomes. The melanosomal membrane is indeed a very impervious structure which protects the cell from very toxic metabolites (quinones) generated during melanogenesis.
Another approach to inhibit skin melanogenesis is to act on the process of tyrosinase maturation. Tunicamycin has for instance been proposed to this end, since this compound disturbs tyrosinase glycosylation which is necessary for its maturation and for its migration from the Golgi to the melanosomes. However, the inhibition of glycosylation is unspecific and associated with a number of side effects rendering the cosmetic use of this compound unsuitable. Similarly, other agents have been proposed which are able to modify the conformation of tyrosinase so as to lower its stability and direct it to the degradation pathways (ER-associated degradation or through the endosomal/lysosomal system). However, the major drawback of this approach is that it may also interfere with the maturation of other proteins and thus alter a number of biological mechanisms other than melanogenesis. Again, this is not conceivable for a cosmetic product.